FDA, Health Organizations to Study Safety of Medications Taken During PregnancyNew collaborative research program to study effects on mothers and their babies

A new research program called the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) will fund research to study the effects of prescription medications used during pregnancy. The program is a collaboration among the U.S. Food and Drug Administration and researchers at the HMO Research Network Center for Education and Research in Therapeutics (CERT), Kaiser Permanente’s multiple research centers and Vanderbilt University.

About two-thirds of women who deliver a baby have taken at least one prescription medication during pregnancy according to a journal article published in the American Journal of Obstetrics and Gynecology. There are very few clinical trials that test the safety of medications in pregnancy due to concerns about the health of the mother and child.

“This program is a great example of FDA and the private sector working together to improve the health of pregnant women and their children,” said Margaret Hamburg, MD, Commissioner of Food and Drugs. "These data will guide regulatory policy and influence medical practice."

To overcome the challenges presented by the lack of clinical trial data about the use of medications during pregnancy, the research program will link health care information for mothers and their babies in each of the participating research sites. Collectively, the 11 participating sites have health care information for about 1 million births over the past seven years (2001-2007). Many of the mothers associated with these births likely used medication during their pregnancies and now, with the program in place, the FDA and participating researchers have a systematic and timely way of retrieving information from this network.

“This collaborative effort creates a unique resource to study the effects of medication in pregnant women and their children,” said Gerald Dal Pan, M.D., director of the Office of Surveillance and Epidemiology at the FDA’s Center for Drug Evaluation and Research. “Results of these studies will provide valuable information for patients and physicians when making decisions about medication during pregnancy.”

The program blends clinical and research expertise and population-based databases from 11 health plan-affiliated research sites including Kaiser Permanente (Northern California, Southern California, Georgia,, Pacific Northwest, and Colorado regions); Harvard Pilgrim Health Care Institute, Group Health Research Institute, HealthPartners, Lovelace Clinic Foundation, the Meyers Primary Care Institute, and Tennessee State Medicaid, and the FDA. The HMO Research Network CERT Data Center at the Department of Population Medicine of Harvard Medical School and Harvard Pilgrim Health Care Institute, led by Richard Platt, M.D., M.S., is the coordinating center for the program.

Lead researchers include Susan Andrade, Sc.D. HMO Research Network William Cooper, M.D., M.P.H. (Vanderbilt); Robert Davis, M.D., M.P.H. (Kaiser Permanente Georgia); Craig Cheetham, Pharm.D.; (Kaiser Permanente Southern California); and De-Kun Li, M.D., Ph.D. (Kaiser Permanente Northern California). The investigators have collaborated on numerous studies related to medication use during pregnancy and birth outcomes, as well as studies on the effects of anti-depressant medications, antibiotics, and cardiovascular medications on birth defects and perinatal outcomes.

Pandemic (H1N1) 2009 - update 81Weekly update30 December 2009 -- As of 27 December 2009, worldwide more than 208 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 12220 deaths.

WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of data.

Situation update:The most active areas of pandemic influenza transmission currently are in central and eastern Europe. Focal increases in rates of ILI/ARI during recent weeks were reported in at least three eastern European countries, Georgia, Montenegro, and Ukraine. A high intensity of respiratory diseases activity with concurrent circulation of pandemic influenza persists in parts of southern and eastern Europe, particularly in Greece, Poland, Bulgaria, Serbia, Ukraine, and the Urals Region of the Russian Federation. In Western Europe, influenza transmission remains active and widespread, but overall disease activity has peaked. At least 13 of 21 countries (testing more than 20 sentinel samples) reported that 30% or more of sentinel specimens were positive for influenza, down from a peak of over 70%. All were influenza viruses detected in Western Europe were pandemic H1N1 2009, however, very small numbers of seasonal influenza viruses, making up less than 1% of all influenza viruses detected, were reported in Russia. In addition, limited available data indicates that active, high intensity transmission is occurring in Northern African countries along the Mediterranean coast (Algeria, Tunisia, and Egypt).

In Central Asia, limited data suggest that influenza virus circulation remains active, but transmission may have recently peaked in some places. In West Asia, Israel, Iran, Iraq, Oman, and Afghanistan also appear to have passed their peak period of transmission within the past month, though both areas continue to have some active transmission and levels of respiratory disease activity have not yet returned to baseline levels.

In East Asia, influenza transmission remains active but appears to be declining overall. Influenza/ILI activity continued to decline in Japan, in northern and southern China, Chinese Taipei, and Hong Kong SAR (China). Slight increases in ILI were reported in Mongolia after weeks of declining activity following a large peak of activity over one month ago. In southern Asia, influenza activity continues to be intense, particularly in northern India, Nepal, and, Sri Lanka. Seasonal influenza A (H3N2) viruses are still being detected in very small numbers in China making up about 2.5% of the influenza A viruses detected there.

In North America, influenza transmission remains widespread but has declined substantially in all countries. In the US, sentinel outpatient ILI activity has returned to the seasonal baseline, and indicators of severity, including hospitalizations, paediatric mortality, and P&I mortality have declined substantially since peaking during late October. Rates of hospitalization among cases aged 5-17 years and 18-49 year far exceeded rates observed during recent influenza seasons, while rates of hospitalizations among cases aged >65 years were far lower than those observed during recent influenza seasons.

In the tropical regions of Central and South America and the Caribbean, influenza transmission remains geographically widespread but overall disease activity has been declining or remains unchanged in most parts, except for focal increases in respiratory disease activity in a few countries.

In the temperate regions of the southern hemisphere, sporadic cases of pandemic influenza continued to be reported without evidence of sustained community transmission.

The Global Influenza Surveillance Network (GISN) continues monitoring the global circulation of influenza viruses, including pandemic, seasonal and other influenza viruses infecting, or with the potential to infect, humans including seasonal influenza. For more information on virological surveillance and antiviral resistance please see the weekly virology update (Virological surveillance data, below).

Weekly update (Virological surveillance data) *Countries in temperate regions are defined as those north of the Tropic of Cancer or south of the Tropic of Capricorn, while countries in tropical regions are defined as those between these two latitudes.

New data suggest that breast cancer patients with HER2- and basal-molecular subtypes are more likely to respond to neoadjuvant chemotherapy than patients with luminal-type molecular subtype characteristics.

The findings were released at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

George Somlo, MD, Co-Director of the Breast Cancer Program at the City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues are assessing the predictive value of Mammaprint scores as well as basal-, luminal-, and HER2- molecular subtype profiling in women with stages II to III and inflammatory breast cancer in order to determine the response to treatment for three different neoadjuvant chemotherapy regimens.

These regimens include docetaxel, doxorubicin, cyclophosphamide (TAC); doxurubicin, cyclophosphamide, and nab--paclitaxel; and carboplatin with or without trastuzumab.

Prior research has shown that pathologic complete response and minimal residual cancer burden after neoadjuvant chemotherapy may predict improved survival, Dr. Somlo and his group wrote in their poster presentation. Thus, improved neoadjuvant chemotherapy regimens in conjunction with molecular markers that predict for both response and/or resistance are needed.

For the ongoing trial, women with stages II-III breast cancer are randomized to receive 6 cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 with filgrastim support (TAC, arm A) versus a novel regimen of A 60 mg/m2 and C 600 mg/m2 given every 2 weeks x 4, followed by 3 weekly doses of carboplatin (AUC 2) and nab-paclitaxel 100 mg/m2 repeated as 28 day cycles x 3 (arm B). Patients with HER2 + BC receive neoadjuvant chemotherapy similar to arm B, but with the addition of 12 weekly doses of trastuzumab given together with carboplatin and nab-paclitaxel (arm C).

Sufficient amounts of breast cancer tissue and good quality RNA for gene array assessment were procured in 64% of the first 90 patients who have undergone pre-treatment core biopsies followed by neoadjuvant chemotherapy and then definitive surgery.

Complete data available in 50 women thusfar reveal that by gene profiling, 28% of the tumors were HER2-type (versus 38% by IHC 3+, or FISH, representing all patients treated on arm C), 26% basal-type, 42% luminal-type, and 4% borderline luminal-type. Poor-prognosis signature by the 70-gene assay was observed in 74% of patients: 92% of HER2-type, 100% of basal-type, and 52% of luminal-type tumors were characterized as poor-risk by the 70-gene assay.

Following neoadjuvant chemotherapy, Symmans RCB scores of 0-1 were documented in 71% of patients with HER2-like, 38% with basal-type, and 28% of patients with luminal-type molecular subtype characteristics.

Overall, the results to date suggest that breast cancer with HER2- and basal-molecular subtypes are more likely to respond to neoadjuvant chemotherapy and are frequently associated with poor-risk characteristics as determined by the 70-gene assay, Dr. Somlo said.

He added that the trial plans to recruit a total of 115 women.

Written by Jill SteinJill Stein is a Paris-based freelance medical writer. Copyright: Medical News Today Not to be reproduced without permission of Medical News Today

NEW YORK – A team of Columbia scientists have discovered two genes that, when simultaneously activated, are responsible for the most aggressive forms of human brain cancer.

This finding was made possible by the assembly of the first comprehensive network of molecular interactions that determine the behavior of these cancer cells, a map so complex and elusive that, until now, it could not be constructed. The discovery may lead to completely novel strategies to diagnose and treat these incurable tumors.

The findings will be published in an advanced online edition of Nature on Dec. 23, 2009, by a team of Columbia scientists led by Antonio Iavarone, M.D., associate professor of neurology in the Herbert Irving Comprehensive Cancer Center, and Andrea Califano, Ph.D., director of the Columbia Initiative in Systems Biology.

The researchers studied a type of human malignancy, called glioblastoma multiforme, which is among the most lethal because it rapidly invades the normal brain producing inoperable brain tumors. Recently, glioblastoma claimed the life of Senator Edward Kennedy only sixteen months after diagnosis.

Before this study, cancer researchers had little idea why glioblastoma is so aggressive. "We now know that two genes – C/EPB and Stat3 – are the disease's master 'control knobs'," said Dr. Iavarone. "When simultaneously activated, they work together to turn on hundreds of other genes that transform brain cells into highly aggressive, migratory cells."

The two genes are active in about 60 percent of all glioblastoma patients and help identify poor-prognosis patients. All patients in the study whose tumors showed activation of both factors died within 140 weeks after diagnosis, while one half of the patients without these factors were still alive.

"The finding means that suppressing both genes simultaneously, using a combination of drugs, may be a powerful therapeutic approach for these patients, for whom no satisfactory treatment exists," said Dr. Califano.

This approach, called combination therapy, is supported by this study since silencing both genes in human glioblastoma cells completely blocked their ability to form tumors when injected in a mouse. Based on these results, the Columbia scientists received a grant from the American Recovery and Reinvestment Act to develop drugs specifically aimed at these genes.

Two Genes Uncovered with a Systems Biology Approach

Biomedical researchers today are like city engineers trying to reduce traffic jams without a street map. Armed only with a list of congested roads, engineers would not be able to locate the traffic jams or find the best way to unclog them. But with a city map in hand, clusters of congestion would immediately become apparent along with possible solutions.

"We are fighting very much the same problem in the post-genomic era," said Dr. Califano. "The human genome project has given biologists a wonderfully comprehensive list of street names – the genes inside every human cell. Unfortunately, it provided virtually no understanding of how all those genes may work together, within highly complex control networks, to operate the cell. In short, biologists need a map of the cell."

Thirty years of laboratory experimentation have revealed glimpses of the complete network. Yet, with trillions of potential interactions among our genes and different network structures in different cells, experimentation alone is unlikely to succeed. Best estimates indicate that only 10 percent of all the molecular interactions in a cell are understood and only a very small fraction of them in any specific cell type.

The Columbia team, which includes physicists and biologists, has for the first time assembled and experimentally validated such a cellular network for a glioblastoma cell, a hugely complex challenge that required several novel approaches drawn from the fields of information theory and computational biology.

"Armed with such a blueprint of the cell machinery, we can now ask pointed questions, such as which genes are responsible for the most deadly features of these tumors," said Dr. Iavarone.

From this blueprint, produced in Dr. Califano's lab, the scientists pinpointed the tumor's two master regulator genes. Experiments conducted by Dr. Iavarone in brain cancer cells and mice then confirmed the accuracy of the network and the importance of the two genes.

"The identification of C/EPB and Stat3 came as a complete surprise to us, since these genes had never been implicated before in brain cancer," said Dr. Iavarone. Based on traditional approaches, their critical role may have eluded researchers for a long time.

"From a therapeutic perspective, it means we are no longer wasting time developing drugs against minor actors in brain cancer," added Dr. Iavarone. "We can now attack the major players."

Given its generality, the new approach has the potential to change the way researchers think not just about cancer but also about many other diseases.

In the last decade, reams of data have been generated by the human genome project and new high-throughput technologies that measure the activity of each gene inside a cell. Yet, the way cancer biologists evaluate this data seemed very biased to the Columbia scientists. Typically, researchers compare data from cancer cells and normal cells and focus on the genes with the greatest change in activity.

It's like investigating a plane crash and blaming the wing because it has the most damage. The actual alterations that caused the crash – like the causes of cancer – may be far more subtle, like a tiny defective control circuit that shows almost no damage.

Instead of focusing on the "damaged wings" of cancer, the new network approach allows biologists to pinpoint causal genes by tracing their downstream effects back to the source.

Indeed, in the case of glioblastoma, the activity of the two master genes was virtually identical in cancer cells compared to normal cells. Yet, like a tiny control switch causing a plane crash, their combined effect turned out to be massive.

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The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital encompasses pre-clinical and clinical research, treatment, prevention and education efforts in cancer. The Cancer Center was initially funded by the NCI in 1972 and became a National Cancer Institute (NCI)–designated comprehensive cancer center in 1979. The designation recognizes the Center's collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic and preventive approaches to cancer. For more information, visit www.hiccc.columbia.edu.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the most comprehensive medical research enterprise in New York City and state and one of the largest in the United States. Columbia University Medical Center is affiliated with NewYork-Presbyterian Hospital, the nation's largest not-for-profit hospital provider. For more information, please visit www.cumc.columbia.edu.

Reported December 30, 2009 Understanding the Genetics of Colon Cancer (Ivanhoe Newswire) -- As researchers and clinicians search for causes and cures for colorectal cancer, 160,000 cases are diagnosed and 57,000 patients die of the disease each year. It is the second leading cause of death from cancer among adults, after lung cancer.

In a recent study, Dr. Sanford Markowitz, professor at Case Western Reserve University School of Medicine and oncologist at Case Medical Center, and co-author, Dr. Monica Bertagnolli, from the Brigham and Women's Hospital, Harvard Medical School, were quoted as saying, "Today's challenges are to understand the molecular basis of individual susceptibility to colorectal cancer and to determine factors that initiate the development of the tumor, drive its progression, and determine its responsiveness or resistance to antitumor agents."

Studies that aid in understanding colorectal cancer on a molecular level have provided genetic testing for high-risk familial forms of the disease, predictive markers for selecting patients for certain classes of drug therapies and molecular diagnostics for the noninvasive detection of early cancers.

For example, patients with inherited mutations in tumor-suppressor genes, such as APC, MLH1, and MSH2, have a very high risk of colorectal cancer and require early and frequent surveillance for colon cancer and often prophylactic surgery.

Patients whose colon cancers have mutations in either RAS or BRAF genes are known not to benefit from treatment with the anti-colon cancer agent Cetuximab.

The development of molecular diagnostics for the early detection of colorectal cancer is emerging as an important tool in clinical practice. One example is the development of stool DNA tests for early detection of colorectal cancer or advanced adenomas. Stool DNA testing for colorectal cancer has now been added to the cancer-screening guidelines of the American Cancer Society. SOURCE: New England Journal of Medicine, December 17, 2009http://www.ivanhoe.com/channels/p_channelstory.cfm?storyid=23248

Scope and Target Population:The guideline will address the management of chronic pain for physiologically mature adolescents (between 16-18 years) and adults. It can be applied to pediatric populations where noted. It is not intended for the treatment of migraine headaches, cancer pain, advanced cancer pain, or in the context of palliative care or end-of-life management.

Definitions

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (International Association for the Study of Pain).

Acute pain states can be brief, lasting moments or hours, or they can be persistent, lasting weeks or several months until the disease or injury heals. The condition has a predictable beginning, middle and end.

Chronic pain is defined as persistent pain, which can be either continuous or recurrent and of sufficient duration and intensity to adversely affect a patient's well-being, level of function, and quality of life. If the patient has not been previously evaluated, attempt to differentiate between untreated acute pain and ongoing chronic pain. If a patient's pain has persisted for six weeks (or longer than the anticipated healing time), a thorough evaluation for the course of the chronic pain is warranted.-Chronic Pain Syndrome – is at the end of the spectrum of chronic pain. The work group defines this as a constellation of behaviors related to persistent pain that represents significant life role disruption.

Clinical Highlights and Recommendations:-Chronic pain assessment should include determining the mechanisms of pain through documentation of pain location, intensity, quality and onset/duration; functional ability and goals; and psychological/social factors such as depression or substance abuse.

-The goal of treatment is an emphasis on improving function through the development of long-term, self-management skills including fitness and a healthy lifestyle in the face of pain that may persist.

-A patient-centered, multifactorial, comprehensive care plan is necessary, one that includes addressing biopsychosocial factors. Addressing spiritual and cultural issues is also important. It is important to have a multidisciplinary team approach coordinated by the primary care physician to lead a team including specialty areas of psychology and physical rehabilitation.

-Level I treatment approaches should be implemented as first steps toward rehabilitation before Level II treatments are considered.

-Medications are not the sole focus of treatment in managing pain and should be used when needed to meet overall goals of therapy in conjunction with other treatment modalities.

-Careful patient selection and close monitoring of all non-malignant pain patients on chronic opioids is necessary to assess the effectiveness and watch for signs of misuse or aberrant behavior.

Priority Aims:Improve the function of adult patients with chronic pain.

Improve the assessment and reassessment of adult patients with chronic pain utilizing the biopsychosocial model.

Improve the appropriate use of Level I and Level II treatment approaches for adult patients with chronic pain.

Improve the effective use of non-opioid medications in the treatment of adult patients with chronic pain.

Improve the effective use of opioid medications in the treatment of adult patients with chronic pain.

Scope and Target Population:This guideline has been developed for patients of all ages (from infant to very elderly) who have acute pain or may be experiencing acute pain in the future (i.e., planned surgery). This guideline excludes patients with acute cancer pain, labor pain and migraine headache, although many of the guideline's recommendations apply to those groups, as well.

Rather than focus on the cause of the pain (a comprehensive list would fill a textbook) or the setting where the pain is treated (inpatient or outpatient), this guideline focuses on effective treatment based on the physiologic mechanisms of pain transmission (e.g., somatic, visceral, neuropathic). Understanding this should allow clinicians to apply this algorithm to almost any kind of acute pain (no matter what the cause) and in any setting.

We acknowledge that assessments of pain in the preverbal, non-English-speaking and cognitively impaired are challenging. As a result, relevant recommendations will be made in order to enhance assessment of an intervention for all patients. The following definitions are assumed:

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

Acute pain states can be brief, lasting moments or hours, or they can be persistent, lasting weeks or several months until the disease or injury heals.

Chronic pain, is defined as persistent pain, which can be either continuous or recurrent and of sufficient duration and intensity to adversely affect a patient's well-being, level of function, and quality of life. If a patient's pain has persisted for six weeks (or longer than the anticipated healing time), a thorough evaluation for the cause of the chronic pain is warranted.

Clinical Highlights and Recommendations:

Intensity of pain is assessed prior to initiation of appropriate treatment and continually reassessed throughout duration of treatment.

Determine the mechanism of pain (i.e., somatic, visceral, neuropathic) based on the physical examination and detailed history.

Patients often experience more than one type of pain.

Somatic pain is well localized and may be responsive to acetaminophen, cold packs, corticosteroids, localized anesthetic (topical or infiltrate), NSAIDs, opioids and tactile stimulation.

Visceral pain is more generalized and is most responsive to opioid treatment.

Neuropathic pain may be resistant to opioid therapy and consideration should be given to adjuvant therapy such as tricyclic antidepressants and anticonvulsants.

While the emphasis of this guideline is on pharmacologic therapy, multimodal treatment approaches are important to consider because patient satisfaction is high when non-pharmacologic approaches are provided.

Priority Aims:

Improve the assessment and reassessment of all age patients with acute pain by determining the mechanism and intensity of pain.

Improve the treatment of patients (all ages) with acute pain, to include appropriate selection of pharmacologic and/or non-pharmacologic interventions.

Increase the involvement of patients with acute pain of all ages, or their caregiver, in the management of their pain symptoms.

Additional Background:Rather than focus on the cause of pain (a comprehensive list would fill a text book) or the setting where the pain is treated (inpatient/outpatient), this guideline focuses on effective treatment based on the physiologic mechanisms of pain transmission (e.g., somatic, visceral, neuropathic). Understanding this should allow clinicians to apply this algorithm to almost any kind of acute pain in any setting (this guideline excludes patients with acute cancer pain, labor pain, and migraine headache). We acknowledge that assessments of pain in the preverbal, non-English speaking and cognitively impaired are challenging. As a result, relevant recommendations have been made in order to enhance assessment of an intervention for all patients.